Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate
Abstract
:1. Introduction
2. Results and Discussions
2.1. Structure Determination by Single-Crystal X-ray Diffraction
- (a)
- The structure is a hemihydrate (one half water molecule for each ORBI molecule), and the water oxygen atom lies in a special position (lies in the 2-fold axis parallel to the unit cell a axis) of the C2221 space group. Therefore, the two water hydrogen atoms shown in Figure 2 are crystallographic dependent by symmetry.
- (b)
- The ORBI molecule is in its zwitterion form with the carboxylic hydrogen transferred to pyperazine nitrogen. The proton transfer was confirmed by Fourier difference maps, which show the absence of residual electron density close to the oxygen atoms of the carboxylic group and the presence of two large peaks of electronic density close to the pyperazine nitrogen, which clearly reveals the presence of two hydrogens linked to it (Figure 3). Moreover, identical bond lengths are observed for C1-O1 (1.250(3) Å) and C1-O2 (1.251(2) Å), indicating the formation of a carboxylate ion (negative charge resulting from deprotonation is delocalized between the two oxygen atoms).
- (c)
- Since ORBI molecule has two stereocenters (at C15 and C16) and it is crystallized in a non-centrosymmetric space group (Table 1) containing just one molecule in the asymmetric unit, its crystal structure is expected to contain a pure enantiomer [31]. However, this is not the case because the piperazine ring containing the two stereocenters has as internal mirror plane (through N2, N3, and the hydrogens linked to N3) that bisects this moiety. The symmetrical nature arising from the presence of two stereogenic centres with identical substitution but opposite configuration makes ORBI a meso-compound. As highlighted by Hoffmann, meso-compounds can reach the same conformation with a plane of symmetry or a centre of inversion among the continuum of freely accessible conformations [32]. The ORBI C15(R),C16(S) and C15(S),C16(R) isomers are equivalent (superimposable on its internal mirror image) considering the pyperazine moiety. Additionally, because the quinolone and pyperazine rings can freely rotate around the C7-N2 bond, the whole molecules containing the two isomers are also equivalent. ORBI is therefore optically inactive; the contributions of the two stereogenic centres to the Cotton effect compensate for each other [32]. Therefore, the C15(R),C16(S) isomer shown in Figure 2 was arbitrarily chosen.
2.2. ORBI Characterization
2.2.1. Powder X-ray Diffraction
2.2.2. Thermal Analysis
2.2.3. Infrared Spectroscopy with Attenuated Total Reflectance by Fourier Transform (FTIR-ATR)
2.3. Interconversion Study between ORBI Anhydrous and Hemihydrate Forms
2.4. Characterization of ORBI Tablets
2.5. Solubility Studies of Hemihydrated and Anhydrous Forms of ORBI
3. Materials and Methods
3.1. Chemicals
3.2. Crystal Preparation
3.3. Structural Determination by X-ray Diffraction for Single Crystals
3.4. Powder X-ray Diffraction Analysis
3.5. Infrared Spectroscopy with Attenuated Total Reflectance by Fourier Transform (FTIR-ATR)
3.6. Thermal Analysis
3.7. Interconversion Study between ORBI Anhydrous and Hemihydrate Forms
3.8. ORBI Quantification
3.9. Solubility Studies
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
ORBI | orbifloxacin |
API | Active Pharmaceutical Ingredient |
SCXRD | Single-Crystal X-ray Diffraction |
PXRD | Powder X-ray Diffraction |
TG/DTA | Thermogravimetric/Differential Thermal Analysis |
FTIR-ATR | Fourier transform infrared spectroscopy-Attenuated Total Rectance |
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Parameter | Value |
---|---|
Empirical Formula | C19H20F3N3O3. 1/2H2O |
Formula Weight (g∙mol−1) | 404.4 |
Temperature (K) | 150 (2) |
Wavelength (Å) | 0.71073 |
Crystal System | Orthorhombic |
Space group | C2221 |
Cell parameters (Å, °) | a = 8.4713(4); b = 20.0456(7); c = 21.4550(7); α = β = γ = 90 |
Cell Volume (Å3) | 3643.3(2) |
Z; Calc. density (g∙cm−3) | 8; 1.474 |
Absorption coefficient (mm−1) | 0.123 |
F(000) | 1688 |
Crystal size (mm3) | 0.25 × 0.15 × 0.10 |
θ-range (°) | 1.90 a 29.49 |
Index ranges | −11≤ h ≤ 11; −27 ≤ k ≤ 25; −29 ≤ l ≤28 |
Reflexions collected/unique | 22,842/4627 [R(int) = 0.0281] |
Completeness to θmax = 29.49 (%) | 100 |
Refinement method | Full-matrix least-squares on F2 |
Data/restraints/parameters | 4627/0/267 |
Goodness-of-fit on F2 | 1.041 |
R1/wR2 for I > 2σ(I) | R1 = 0.0357, wR2 = 0.0883 |
R1/wR2 for all data | R1 = 0.0428, wR2 = 0.0938 |
Largest diff. peak/hole (e∙ų) | 0.287 and −0.202 |
D-H···A | d(D-H) | d(H···A) | d(D···A) | <(D-H-A) |
---|---|---|---|---|
O5ii-H5ii···O2ii | 0.92(8) | 1.98(8) | 2.854(3) | 159(7) |
N3-H3a···O1i | 0.88(3) | 1.86(3) | 2.720(2) | 164(2) |
N3-H3b···O2ii | 0.86(3) | 1.94(3) | 2.714(2) | 150(2) |
N3-H3b···O3ii | 0.86(3) | 2.35(3) | 2.955(2) | 128(2) |
C11-H11···O2iv | 0.98 | 2.42 | 3.382(3) | 168.6 |
Media | Hemihydrate (g·L−1) | SD (g·L−1) | Solubility * | Anhydrous (g·L−1) | SD (g·L−1) | Classification * | Anhydrous/ Hemihydrate (%) | Final pH † |
---|---|---|---|---|---|---|---|---|
Water | 1.32 | 0.0678 | SS | 1.38 | 0.06634 | SS | 4.38 | 7.0 |
pH 7.5 | 1.58 | 0.0644 | SS | 1.64 | 0.05327 | SS | 3.80 | 7.5 |
pH 6.8 | 1.52 | 0.039 | SS | 1.59 | 0.07758 | SS | 4.60 | 7.0 |
pH 5.8 | 1.73 | 0.0601 | SS | 1.98 | 0.07915 | SS | 14.45 | 6.0 |
HCl 0.01 mol·L−1 | 6.30 | 0.1739 | SS | 10.33 | 0.29854 | SP | 63.97 | 6.0 |
pH 4.5 | 10.41 | 0.5007 | SP | 14.24 | 0.5539 | SP | 36.79 | 4.5 |
HCl 0.1 mol·L−1 | 22.24 | 0.7506 | SP | 26.23 | 1.0623 | SP | 17.94 | 2.0 |
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Santos, O.M.M.; Freitas, J.T.J.; Cazedey, E.C.L.; Araújo, M.B.d.; Doriguetto, A.C. Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate. Molecules 2016, 21, 328. https://doi.org/10.3390/molecules21030328
Santos OMM, Freitas JTJ, Cazedey ECL, Araújo MBd, Doriguetto AC. Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate. Molecules. 2016; 21(3):328. https://doi.org/10.3390/molecules21030328
Chicago/Turabian StyleSantos, Olimpia Maria Martins, Jennifer Tavares Jacon Freitas, Edith Cristina Laignier Cazedey, Magali Benjamim de Araújo, and Antonio Carlos Doriguetto. 2016. "Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate" Molecules 21, no. 3: 328. https://doi.org/10.3390/molecules21030328